The present invention relates to the novel, where appropriate amphiphilic, glyceryl nucleotides, to their preparation and to compositions for treating cancer diseases and infectious diseases.
Nucleoside analogs which exhibit defined structural features have proved to be valuable drugs in the chemotherapy of cancer diseases and infectious diseases caused by viruses (Advanced Drug Delivery Review (1996) 19, 287). However, the therapeutic effect of the nucleoside analogs is only seen when the nucleoside analogs, which are themselves inactive, are taken up by the cell, as prodrugs, and then anabolized into the actual active compounds, i.e. the 5xe2x80x2-triphosphate derivatives of the nucleoside analog. These nucleotides stop DNA replication and/or block the reverse transcriptase. Nucleoside analogs, such as 1-xcex2-D-arabinofuranosylcytosine (araC) and 5-fluoro-2xe2x80x2-deoxyuridine (5FdU), which prevent DNA replication, are effective against malignant diseases of the hematopoietic cells and against solid tumors. Dideoxynucleoside analogs, such as 3xe2x80x2-azido-2xe2x80x2,3xe2x80x2-dideoxythymidine (AZT), 2xe2x80x2,3xe2x80x2-dideoxycytidine (ddC), 2xe2x80x2,3xe2x80x2-dideoxyinosine (ddl), 3xe2x80x2-thia-2xe2x80x2,3xe2x80x2-dideoxycytidine (3TC) and 2xe2x80x2,3xe2x80x2-didehydro-2xe2x80x2,3xe2x80x2-dideoxythymidine (d4T), are particularly suitable for the therapy of infection with HIV.
A nonnucleosidic antiviral active compound, such as the trisodium salt of phosphonoformic acid (Foscarnet) blocks the pyrophosphate-binding site of the viral polymerase. This prevents viruses such as herpes simplex virus, HIV virus and human cytomegalovirus from replicating. Amphiphilic glyceryl derivatives of Foscamet, which are better able to traverse the membrane, contribute to optimizing the virus therapy (Antivir. Chem. and Chemother. (1998) 9, 33).
Because of the development of resistance during the course of chemotherapy, which occurs particularly rapidly in the case of HIV treatment, the progression of the disease can only be retarded in the long term by using a combination therapy. In such a therapy, several antiviral active compounds are administered jointly (Schweiz. Med. Wochenschr. (1997) 127, 436). Because the therapy regime which has to be imposed on the patients in the case of combination therapy is strict, patient compliance is low. The therapeutic success which is achieved is therefore well below the possible success which could be achieved with the high potential which the available drugs possess. (AIDS 1998 Diagnostik und Therapie (Diagnosis and Therapy, Steinhauser publishing company).
At best, administration of a form in which, for example, the two nucleosidic prodrugs (AZT and 3TC) are present as a mixture, as is the case with Combivir, only makes combination therapy more practicable for patients. However, it is scarcely possible to achieve an improved effect with such mixtures since the uptake of the prodrugs by the cell is not increased and nor is there any optimization of their anabolism to give the active compound.
On the other hand, it is possible to optimize combination therapy decisively using amphiphilic combination preparations in which two antiviral nucleoside analogs are coupled by way of a phosphodiester bond (EP 0 642 527 B 1). A certain disadvantage of these ampiphilic dinucleoside phosphate analogs is that, when a desired enzymic cleavage of the phosphodiester bond takes place, only one monomer unit is in each case released as an active nucleotide analog whereas the second monomer unit of the combination preparation inevitably remains as a nucleoside analog which is in itself inactive. If the cell does not anabolize this nucleoside analog to give the active nucleotide analog, up to 50% of the administered dimer can then not be used therapeutically and is consequently inactive. An additional disadvantage of these amphiphilic combination preparations is that at least one of the two coupled nucleoside analogs has to possess a lipophilic radical so as to ensure that the resulting dimer is amphiphilic. Consequently, two nucleoside analogs which are suitable for combination therapy, but neither of which can be lipophilized, cannot be converted into amphiphilic dimers and used as a combination preparation in therapy.
The object of this invention is to make available novel combination preparations which can be used to combat cancer diseases and infections even more effectively. This object is achieved by means of novel glyceryl nucleotides which, on being metabolized, are in each case able to liberate two active compounds simultaneously such that the advantages of the abovementioned combination of two active compounds are fully exploited. In order to prepare the novel glyceryl nucleotides, preference is given to covalently bonding either two therapeutically active nucleoside derivatives to each other, or a nucleoside derivative to phosphonoformic acid or its salt form (Foscarnet), by way of a glycerol lipid backbone.
The invention firstly relates to glyceryl nucleotides of the formula la 
in which
a) one of the radicals A1, A2 and A3 is a hydrogen atom, or a radical which is selected from hydroxyl, mercapto, alkyl, alkenyl, polyoxyalkenyl, aryl, acyl, alkyloxy, alkenyloxy, polyoxyalkenyloxy, acyloxy, aryloxy, alkylthio, alkenylthio, acylthio and arylthio, where the alkyl, alkenyl and acyl are optionally substituted by 1 to 3 aryl radicals; and
b1) two of the remaining radicals A1, A2 and A3 are two nucleoside groups which differ from each other, each of which nucleoside groups is linked to the carbon atom of the glyceryl chain by way of a physiologically cleavable phosphorus-containing bridging group; or
b2) one of the remaining radicals A1, A2 and A3 is a nucleoside group and the other of the remaining radicals is a hydroxycarbonyl group, each of which is linked to the carbon atom of the glyceryl chain by way of a physiologically cleavable phosphorus-containing bridging group;
where at least one of the nucleoside groups is not a naturally occurring nucleoside group, which nucleoside group is optionally substituted, in its base moiety, on one or more ring atoms and/or on one or more side groups, such as amino side groups, by one or more radicals which are selected from hydroxyl, amino, halogen, alkyl, alkenyl, polyoxyalkenyl, aryl, acyl, alkyloxy, alkenyloxy, polyoxyalkenyloxy, acyloxy, aryloxy, alkylthio, alkenylthio, acylthio and arylthio, where the alkyl, alkenyl and acyl radicals are optionally substituted by 1 to 3 aryl radicals or halogen atoms; and which nucleoside group is optionally substituted, once or more than once, in its carbohydrate moiety, by substituents which are selected from hydrogen, halogen, such as F, Cl, Br and I, hydroxyl, ethynyl and azido, optionally possesses a heteroatom, which is selected from S, N and O, in place of a carbon atom, and optionally contains one or two non-adjacent Cxe2x95x90C double bonds;
in racemic or enantiomerically pure form, and to the pharmaceutically tolerated salts of these compounds.
The nucleoside groups which do not occur naturally and which are present in the compounds according to the invention are derived from nucleosides (nucleoside derivatives) which comprise a heterocyclic radical (base moiety) which is linked N-glycosidically or O-glycosidically to a sugar radical (carbohydrate moiety). They differ from the naturally occurring nucleosides, adenosine, guanosine, cytidine, uridine and thymidine and the corresponding deoxynucleosides in the carbohydrate moiety and/or in the base moiety.
The sugar radical of the nucleoside or nucleoside derivative which does not occur naturally is derived from a hexose or heptose, preferably from a pentose, such as deoxyribose or ribose. Where appropriate, single or several protons or hydroxyl groups can be substituted or eliminated in the sugar radical. In this connection, suitable substituents are selected from the abovementioned substituents hydrogen, halogen, such as F, Cl, Br and I, hydroxyl, ethynyl and azido. Where appropriate, a heteroatom, selected from S, N and O, can be present in place of a carbon atom, and, where appropriate, the sugar radical can contain one or two non-adjacent Cxe2x95x90C double bonds.
The base moiety of the nucleoside or nucleoside derivative which does not occur naturally is the radical of a mononuclear or binuclear heterocyclic base which is composed of one or two four- to seven-membered rings which, together, contain at least one ring heteroatom, such as one to six heteroatoms which are selected from N, S and O, in particular N and O. Examples of such bases are the purine and pyrimidine bases adenine, guanine, cytosine, uracil and thymine. Other examples of usable bases are pyrrole, pyrazole, imidazole, aminopyrazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole, pentazole, pyridone, piperidine, pyridine, indole, isoindole, pyridazine, indoxyl, isatin, pyrazine, piperazine, gramine, tryptophan, kynurenic acid, tryptamine, 3-indoleacetic acid, carbazole, indazole, 1,3,5-triazine, 1,2,4-triazine, 1,2,3-triazine and tetrazine. Preferred bases are adenine, guanine, cytosine, uracil and thymine; and also 1,2,3-triazole, 1,2,4-triazole and tetrazole. Where appropriate, said bases can be substituted once or more than once, such as once to four times, in particular once or twice, by the abovementioned radicals hydroxyl, amino, halogen, alkyl, alkenyl, polyoxyalkenyl, aryl, acyl, alkyloxy, alkenyloxy, polyoxyalkenyloxy, acyloxy, aryloxy, alkylthio, alkenylthio, acylthio or arylthio, where the alkyl, alkenyl and acyl radicals are optionally substituted by 1 to 3 aryl radicals or halogen atoms. In this connection, the substitution can take place on a ring heteroatom or, preferably, on a ring carbon atom or a side group, for example an amino side group of the base.
In the compounds of the formula (Ia) according to the invention, the physiologically cleavable, phosphorus-containing bridging groups are preferably derived from phosphodiester groups and their sulfur-containing analogs. In a preferred embodiment, those compounds of the formula Ia are therefore prepared in which nucleoside groups are linked, independently of each other, to the glyceryl radical byway of a bridging group selected from xe2x80x94OP(OZ)(O)Oxe2x80x94, xe2x80x94SP(OZ)(O)Oxe2x80x94, xe2x80x94OP(OZ)(S)Oxe2x80x94 and xe2x80x94SP(OZ)(S)Oxe2x80x94, and the hydroxycarbonyl group is linked to the glyceryl radical by way of a bridging group selected from xe2x80x94OP(OZ)(O)xe2x80x94, xe2x80x94SP(OZ)(O)xe2x80x94 and xe2x80x94SP(OZ)(S)xe2x80x94, in which Z is a proton or a pharmaceutically tolerated cation.
Particular preference is given to those compounds of the formula Ia in which A1, A2 and A3 are selected such that an amphiphilic character is imparted to the molecule. This is achieved by substituting the glyceryl radical or the nucleoside derivative radical(s) by a lipophilic substituent. In this connection, the nucleoside derivative radical preferably carries the lipophilic radical on the base moiety. Examples of such lipophilic radicals which may be mentioned are alkyl, alkenyl, polyoxyalkenyl, aryl, acyl, alkyloxy, alkenyloxy, polyoxyalkenyloxy, acyloxy, aryloxy, alkylthio, alkenylthio, acylthio and arylthio, where the alkyl, alkenyl and acyl radicals are optionally substituted by 1 to 3 aryl radicals or halogen atoms.
The lipophilic radical should preferably comprise more than 6, for example 7 to 30 or 10 to 24, carbon atoms.
Examples of suitable aryl radicals which may be mentioned are: phenyl, naphthyl and benzyl.
Examples of suitable alkyl radicals which may be mentioned are straight-chain or branched radicals having from 1 to 24 C atoms, such as methyl, ethyl, i- or n-propyl, n-, i-, sec- or tert-butyl, n- or i-pentyl; and, in addition, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, n-tridecyl, n-tetradecyl, n-pentadecyl and n-hexadecyl, octadecyl, docosanyl, and also the singly or multiply branched analogs thereof.
Examples of suitable alkenyl radicals are the singly or multiply, preferably singly or doubly, unsaturated analogs of the abovementioned alkyl radicals having from 2 to 24 carbon atoms, where the double bond can be located in any position in the carbon chain.
Examples of suitable polyoxyalkenyl radicals are derived from C2-C4-alkylene oxides, which can comprise from 2 to 12 repeating alkylene oxide units.
Examples of suitable acyl radicals are derived from straight-chain or branched C1-C24-monocarboxylic acids which are optionally unsaturated once or more than once and optionally substituted. For example, usable acyl radicals are derived from the following carboxylic acids: saturated acids, such as formic, acetic, propionic and n- and i-butyric acid, n- and i-valeric acid, caproic acid, enanthic acid, caprylic acid, pelargonic acid, capric acid, undecanoic acid, lauric acid, tridecanoic acid, myrisuc acid, pentadecanoic acid, palmitic acid, margaric acid, stearic acid, nonadecanoic acid, arachidic acid, behenic acid, lignoceric acid, cerotinic acid and melissic acid; singly unsaturated acids, such as acrylic acid, crotonic acid, palmitoleic acid, oleic acid and erucic acid; and doubly unsaturated acids, such as sorbic acid and linoleic acid. If the fatty acids contain double bonds, the latter can then be present either in the cis or trans form.
Examples of suitable alkyloxy, acyloxy, aryloxy, alkenyloxy and polyoxyalkyleneoxy radicals are the oxygen-terminated analogs of the abovementioned alkyl, acyl, aryl, alkenyl and polyoxyalkylene radicals.
Examples of suitable alkylthio, alkenylthio, acylthio and arylthio are the corresponding sulfur-terminated analogs of the above alkyloxy, alkenyloxy, acyloxy and aryloxy radicals.
The invention relates, in particular, to preferably amphiphilic glyceryl nucleotides of the formula I 
in racemic and enantiomerically pure form, in which the radical A and the two phosphoric acid residues can be linked, in aryl arbitrary sequence, to the C atoms C1, C2 and C3 of the glycerol backbone;
X1, X2, X3 and X4 are identical or different and are oxygen and sulfur;
A is alkyl, hydroxyl, thiol or an alkoxy, alkylthio, alkylcarboxy or alkylthiocarboxy group, where the alkyl radicals are linear or branched, possess 1-24 C atoms and up to 2 double bonds; and can be substituted by from 1 to 3 aromatic radicals;
Z is hydrogen or the corresponding salt of the acid form of this compound;
N1 or N2 is hydroxycarbonyl or its salt form; and the other of the N1 and N2 radicals is a D- or L-configured nucleoside derivative of the formula II, III and IV, and the two radicals N1 and N2 are different when they are both a D- or L-configured nucleoside derivative of the formulae II, III, and IV, 
where
Y is oxygen or sulfur;
R1 is a hydroxyl, amino, acylated, alkylated or polyoxyethylene-substituted amino group, whose acyl or alkyl radical is linear or branched, possesses 1-24 C atoms and up to 2 double bonds, and can be substituted by an aromatic radical;
R2 is hydrogen, halogen, an amino or hydroxyl group, a bromovinyl group or a linear or branched C1 to C24 alkyl radical;
R3, R4, R5, R6, R7 and R8 are identical or different and are hydrogen, halogen, hydroxyl, ethynyl or azido;
and one of the radicals R3 to R8 is oxygen, by way of which the nucleoside derivative is linked to the glyceryl phosphate, and two of the radicals R3 to R6 are dispensed with when a is a Cxe2x95x90C double bond.
The radicals A, R1 and R2 in formula I are preferably selected such that a compound having an amphiphilic character is obtained.
If A is an alkoxy radical, preference is then given to radicals having from 12 to 24 C atoms, such as the hexadecyloxy radical, the octadecyloxy radical or the docosanyloxy radical.
If A is a carboxylic acid radical, preference is then given to radicals having from 12 to 24 C atoms, such as the palmitic acid radical, the stearic acid radical or the behenic acid radical.
If A is an alkyl radical, preference is then given to radicals having from 12 to 24 C atoms, such as the hexadecyl radical, the 9octadecenyl radical, the octadecyl radical or he docosanyl radical.
If R1 is an alkylated amino group, its alkyl radical is then preferably a radical having from 12 to 24 C atoms, such as a hexadecyl radical or an octadecyl radical; if R1 is an acylated amino group, the acyl radical is then preferably a radical having from 12 to 24 C atoms, such as a palmitoyl radical, an oleoyl radical or a behenoyl radical.
R2 is preferably hydrogen, halogen, methyl or ethyl; R3, R4, R5, R6 and R7 are preferably azido, hydrogen, fluorine, ethynyl or hydroxyl; and R8 is preferably a hydroxyl group. However, R8 is particularly preferably an oxygen atom by way of which the nucleoside radical is bonded to the P atom of the bridging group.
If one of the two radicals N1 and N2 is a hydroxycarbonyl radical, preference is then given to the other radical being a nucleoside derivative of the formula II or IV.
Other preferred groups of compounds are:
a) compounds of formula (I), in which
X1, X2, X3 and X4 are an oxygen atom;
the C1 atom of the glycerol backbone of the formula I is linked to the radical A, where A is hydroxyl, octadecyl, octadecyloxy, docosyloxy or behenoyloxy, palmitoyl or oleoyl;
the C2 atom of the glycerol backbone of the formula I is linked to N2 by way of a phosphodiester bridge, where N2 is a nucleoside derivative radical of the formula II, III or IV, in which
Y is an oxygen atom;
R1 is a hydroxyl, amino, octadecylamino, docosylamino, palmitoylamino, oleoylamino or behenoylamino group;
R2 is methyl, ethyl, hydrogen or halogen;
R3 to R8 possess the abovementioned meanings, where one of the radicals
R3, R4, R5, R6 and R8 is an oxygen atom by way of which the nucleoside derivative radical N2 is linked to the phosphorus atom, and
the C3 atom of the glycerol backbone of the formula I is linked to the hydroxycarbonylphosphonate radical in its free or salt form.
b) Compounds of the formula I according to group a), in which, in particular,
N2 is a nucleoside derivative radical of the formula II or IV, in which
R1 is an amino, palmitoylamino or hydroxyl group;
R2 is hydrogen, methyl or ethyl;
R3, R4, R and R7 are hydrogen;
R6 is hydrogen, fluorine or azido, and
R8 is an oxygen atom by way of which the N2 is linked to the phosphorus atom.
c) Compounds of formula I, in which
X1, X2, X3 and X4 are an oxygen atom;
A is palmitoyloxy, oleoyoxyl or octadecyloxy and is linked to the C2 atom of the glycerol backbone of the formula I, and
N1 and N2 are different and are a nucleoside derivative radical of the formulae II, III and IV.
d) Compounds of the formula I according to group c), in which, in particular,
N1 is a, preferably L-configured, nucleoside derivative radical of the formula
in which
R1 is an amino or palmitoylamino group;
R2, R3 and R4 are hydrogen, and
R8 is an oxygen atom by way of which the N1 is linked to the phosphorus atom in position C1 or C3 of the glyceryl diphosphate backbone of the formula I;
and N2 is a nucleoside derivative radical of the formula III or IV.
e) Compounds of the formula I according to group c), in which, in particular,
N2 is a nucleoside derivative radical of the formula IV in which
R1 is an amino, palmitoylamino or hydroxyl group;
R2 is hydrogen or methyl;
R3, R4, R5 and R7 are hydrogen;
R6 is hydrogen, fluorine or azido, and
R8 is an oxygen atom by way of which the N2 is linked to the phosphorus atom in position C1 or C3 of the glyceryl diphosphate backbone of the formula I.
f) Compounds of the formula I according to group c), in which, in particular,
N1 is a nucleoside derivative radical of the formula II or IV, and
N2 is a nucleoside derivative radical of the formula III,
in which, in each case,
R1 is hydroxyl;
R2 to R7 are hydrogen; and
R8 is an oxygen atom by way of which the N1 or N2 is linked to the glycerol-1,3-diphosphate backbone of the formula I.
g) Compounds of the formula I according to group c), in which, in particular,
N1 and N2 are a nucleoside derivative radical of the formula IV,
in which, in N1,
R1 is an amino, palmitoylamino or octadecylamino group;
R2, R5 and R7 are hydrogen;
R3, R4 and R8 are identical or different and are hydrogen, hydroxyl or fluorine;
and in which, in N2,
R1 is a hydroxyl group;
R2 is methyl or halogen;
R3, R 4, R5 and R7 are hydrogen, where two vicinal radicals thereof are optionally dispensed with if a double bond is present in position a;
R6 is hydrogen, fluorine, azido or hydroxyl; and
R8 in N1 and N2 is in each case an oxygen atom by way of which the N1 and N2 are linked to the glycerol-1,3-diphosphate backbone.
h) Compounds of the formula I according to group G, in which, in particular, in N1 and N2,
R1 is identical or different and is a hydroxyl group or an amino group;
R2 is identical or different and is hydrogen or methyl;
R4, R5 and R7 are hydrogen;
R6 is azido in N1 and fluorine in N2; and
R8 is the oxygen atom by way of which the N1 and N2 are linked to the glycerol-1,3-diphosphate backbone.
i) Compounds of the formula I according to group g), in which, in particular, in N1,
R1 is an amino or palmitoylamino group,
R2 and R7 are hydrogen;
R3 and R4 are fluorine, hydrogen or hydroxyl,
R5 is hydrogen or an ethynyl radical,
R6 is hydroxyl, and
xe2x80x83in which, in N2,
R1 is hydroxyl,
R2 is fluorine,
R3, R4, R5 and R7 are hydrogen;
R6 is hydroxyl, and
R8 in N1 and N2 is in each case an oxygen atom by way of which N1 and
N2 are linked to the glycerol-1,3-diphosphate backbone.
The novel, preferably amphiphilic, glyceryl nucleotides of the formula Ia can be prepared by a compound of the formula Ib 
in which
one of the radicals A1B, A2B and A3B is a hydroxyl, mercapto, hydrogen phosphonate or thiohydrogen phosphonate group, and the other two radicals possess the meanings given above for A1, A2 and A3, where at least one of the two radicals is a nucleoside group in accordance with the above definition,
a) being condensed, in the presence of an acid chloride, with a nucleoside or nucleoside derivative in accordance with the abovementioned definition, where the nucleoside derivative additionally carries a hydrogen phosphonate or thiohydrogen phosphonate group if one of the radicals A1B, A2B and A3B is a hydroxyl group or a mercapto group; and the resulting product being oxidized; or
b) being reacted with (ethoxycarbonyl)dichlorophosphonate and the acid chloride and ethoxy groups subsequently being hydrolyzed under alkaline conditions.
The novel, preferably amphiphilic, glyceryl nucleotides of the formula I, in which N1 and N2 are a D- or L-configured nucleoside derivative, can be prepared by a compound of the formula V 
in which the radicals A, XB and the phosphoric acid radical can be linked in any arbitrary sequence to the C1-, C2- and C3 atoms of the glycerol backbone; the radicals A, X2, X3, X4, N2 and Z have the given meanings; and X2B is a hydroxyl, thiol, hydrogen phosphonate or thiohydrogen phosphonate group;
being condensed with a nucleoside derivative of the above formula II, III or IV, in which the radicals R1 to R8 have the given meanings, and, in addition, R8 can also be 4-mono-, 4,4xe2x80x2-dimethoxytriphenylmethoxy, hydrogen phosphonate or thiohydrogen phosphonate; R3, R4, R5 and R6 can additionally be a linear or branched carboxyl radical which possesses 1-24 C atoms and which can be substituted by a phenyl radical; and one of the radicals R3, R4, R5, R6 and R8 is always hydrogen phosphonate or thiohydrogen phosphonate if, in a compound of the formula V, X2B is hydroxyl or thiol, but, on the other hand, none of these radicals is hydrogen phosphonate or thiohydrogen phosphonate if X2B is hydrogen phosphonate or thiohydrogen phosphonate; in the presence of an acid chloride, and subsequently oxidized.
The condensation takes place particularly satisfactorily in the presence of acid anhydrides or acid halides, such as, in particular, pivaloyl chloride, at from xe2x88x9280xc2x0 C. to +100xc2x0 C., for example at about 0-20xc2x0 C. The oxidation takes place particularly satisfactorily at from xe2x88x9280xc2x0 C. to +100xc2x0 C., for example at about 0-20xc2x0 C., with a) the Pxe2x80x94H bond being oxidized to a Pxe2x95x90O bond with iodine in aqueous organic solvents, or b) the Pxe2x80x94H bond being oxidized to a Pxe2x95x90S bond with S8 in triethylamine/CS2.
After oxidizing and working up chromatographically, the 4-mono- or 4,4xe2x80x2-dimethoxytriphenylmethyl group is replaced with hydroxyl. If required, acyl radicals are converted hydrolytically into mercapto, hydroxyl and/or amino groups.
The novel, preferably amphiphilic, compounds of the formula 1, in which N1 is a hydroxycarbonyl radical which is bonded in its acid or salt form, can be prepared by reacting a compound of the formula V, in which B is hydrogen, with (ethoxycarbonyl) phosphoryl dichloride in a manner known per se. The reaction takes place particularly successfully in mixtures with halogenated hydrocarbons, such as, in particular, pyridine/chloroform, acetonitrile/chloroform or pyridine/methylene chloride and acetonitrile/methylene chloride, and trimethyl phosphate at from xe2x88x9210xc2x0 C. to +80xc2x0 C., for example at about 0-10xc2x0 C. After reacting and working up chromatographically, the acid chloride group and the ethoxy group are changed into hydroxyl groups or corresponding salt forms by subsequent hydrolysis under alkaline conditions (J. Med. Chem. (1986) 29, 1389).
The compounds of the formula V which are used as starting material can be prepared by condensation of a compound of the formula VI 
in which the radicals
A, X2R9 and X3B can be linked in any arbitrary sequence to the C1, C2 and C3 atoms of the glycerol backbone;
A and X2 have the abovementioned meanings;
R9 is 4-mono- or 4,4xe2x80x2-dimethoxytriphenylmethyl or a linear or branched acyl radical which possesses 1-24 C atoms and which can be substituted by an aromatic radical; the radical X3B is a hydroxyl, thiol, hydrogen phosphonate orthiohydrogen phosphonate group;
with a nucleoside derivative of the formula II, III or IV, in which the radicals R1-R8 have the abovementioned meanings,
where one of the radicals R3, R4, R5, R6 and R8 is also always hydrogen phosphonate or thiohydrogen phosphonate if, in a compound of the formula VI, the radical X3B is hydroxyl or thiol, but, on the other hand, none of the radicals is hydrogen phosphonate or thiohydrogen phosphonate if, in a compound of the formula VI, X3B is hydrogen phosphonate or thiohydrogen phosphonate;
in the presence of an acid chloride and subsequently oxidizing with iodine or sulfur in a manner known per se (Tetrahedron Lett., (1986) 27, 469; ibid. 5575).
After the chromatographic working up, the 4-mono- or 4xe2x80x2,4xe2x80x2-dimethoxytriphenylmethyl radical is replaced with hydrogen under acid conditions, while the acyl radical is replaced with hydrogen under alkaline conditions.
The starting materials which are required for the reactions are known substances or can be prepared in analogy with known methods (Hel. Chim. Acta (1982) 65, 1059; Liebigs Ann. Chem. (1991) 765; ibid. (1996) 365; Antivir. Chem and Chemother. (1998) 9, 33. J. C. S. Perkin 1 (1982) 11 71; Makromol. Chem. (1986) 187,809; Tetrahedron Left. (1986) 27, 2661).
The compounds according to the invention can have an amphiphilic character or a non-amphiphilic character. However, amphiphilic compounds are particularly preferred.
The conversion, according to the invention, of Foscamet and the therapeutically active nucleoside analogs into amphiphilic glyceryl nucleotides brings about a marked alteration in pharmokinetic behavior. As a result, the dose to be administered can be surprisingly increased in comparison with that of the respective monomer without this, at the same time, leading to any amplification of all the toxic side effects of these highly potent drugs. In addition, amphiphilic glyceryl nucleotides still have an effect even in the presence of resistance to the respective monomeric nucleoside analogs.
The amphiphilic character of the amphiphilic glyceryl nucleotides according to the invention makes it possible to implement a variety of administration schemes. The lipophilic region of the glyceryl nucleotides results in the active compounds being stably incorporated into liposomes together with matrix lipids, promotes the cell uptake of the amphiphilic glyceryl nucleotides which are dissolved in water, and at the same Ume protects them from an enzymic hydrolysis which is too rapid. The hydrophilic region enables the active compounds to be water-soluble as well, presumably by way of micelle formation. The advantage of the alternative possibility of administering the amphiphilic glyceryl nucleotides is that the desired slow-release effect of the dimers is achieved in aqueous solutions as well as in a liposome dispersion, which means that there is no need to rely exclusively on liposome technology but that this technology can be used if required, something which is in turn not readily possible in the case of active compounds which are only soluble in water.
Another advantage of the amphiphilic glyceryl nucleotides according to the invention is that they can be incorporated into liposomes together with differing quantities of one or more other active compounds, with this resulting in synergistic effects. Using these amphiphilic glyceryl nucleotides, and/or in a composition together with a biologically tolerated excipient, and/or using remedies which comprise the compounds according to the invention at least in one or more of the compositions, it is possible to optimize the therapy of cancer diseases and infectious diseases caused by viruses.
In general, the compounds according to the invention are employed in the form of pharmaceutical remedies for treating an individual, preferably a mammal, in particular a human. Thus, the compounds are usually administered in the form of pharmaceutical compositions which comprise a pharmaceutically tolerated excipient together with at least one nucleoside phosphate analog according to the invention, where appropriate a mixture of several compounds according to the invention as well, and, where appropriate, additional active compounds which can be used for the particular therapeutic effect which is desired. These compositions can be administered, for example, orally, rectally, transdermally, subcutaneously, intravenously, intramuscularly or intranasally.
Examples of suitable pharmaceutical formulations are solid medicinal forms, such as powders, granules, tablets, lozenges, sachets, cachets, sugar-coated tablets, capsules, such as hard and soft gelatin capsules, suppositories or vaginal medicinal forms; semisolid medicinal forms, such as ointments, cremes, hydrogels, pastes or plasters, and also liquid medicinal forms, such as solutions, emulsions, in particular oil-in-water emulsions, suspensions, for example lotions, injection and infusion preparations and eye and ear drops. Implanted slow-release devices can also be used for administering compounds according to the invention. It is furthermore possible to use liposomes, microspheres or polymer matrices as well.
Compounds according to the invention are usually mixed or diluted with an excipient when preparing the compositions. Excipients can be solid, semisolid or liquid materials which serve as a vehicle, carrier or medium for the active compound.
Suitable excipients include, for example, lactose, glucose, sucrose, sorbitol, mannitol, starches, gum arabic, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup and methyl cellulose. In addition, the formulations can comprise pharmaceutically acceptable carriers or customary auxiliary substances, such as lubricants, for example talc, magnesium stearate and mineral oil; wetting agents; emulsifying and suspending agents; preservatives, such as methyl- and propylhydroxybenzoates; antioxidants; antiirritants; chelating agents; coating auxiliaries; emulsion stabilizers; film formers; gel formers; odor masking agents; taste corrigents; resins; hydrocolloids; solvents; solubilizing agents; neutralizing agents; permeation accelerators, pigments; quatemary ammonium compounds; regreasing and hypergreasing agents; ointment, cream or oil bases; silicone derivatives; spreading auxiliaries; stabilizers, sterilizing agents; suppository bases, tablet auxiliaries, such as binders, fillers, lubricants, disintegrants or coatings; propellants; desiccants, opacifiers; thickeners; waxes; emollients; white mineral oils. A formulation in this regard is based on specialist knowledge, as presented, for example, in H. P., Lexikon der Hilfsstoffe fxc3xcr Pharmazie, Kosmetik und angrenzende Gebiete, (Encyclopedia of auxiliary substances for pharmacy, cosmetics and related areas), 4th edition, Aulendorf: ECV-Edition-Kantor publishing company, 1996.
A variety of compositions are prepared in order to ensure that the compounds according to the invention are administered as effectively as possible. A feature common to all these compositions is that the compounds according to the invention are combined with an organic carrier.
A preferred embodiment of these compositions provides for the association of the compoundsaccording to the invention in the form of unilamellar to oligolamellar liposomes having a diameter of at most 0.4 xcexcm All the methods which are known per se for preparing liposomes, such as ultrasound, gel chromatography, detergent dialyse and high pressure filtration, can be used for forming the liposomes. The lipophilic radicals which are in each case introduced have an important influence on the size and stability of the liposomes, which are formed from the respective glyceryl nucleotides together with additional lipid components (cf. Liposomes: Physical Structure to Therapeutic Applications in: Research monographs in cell and tissue physiology vol. 7, G. G. Knight editor, Elsevier (1981) as well).
Another preferred possibility of combining the compounds according to the invention with an organic carrier is that of enclosing the compounds in biologically tolerated nanoparticles. Nanoparticles is the name given to organochemical polymers to which the compounds according to the invention are added during the polymerization, such that these compounds are efficiently enclosed in the nanoparticles (cf. Bender et al., Antimicrobial agents and Chemotherapy (1996), 40 (6) 1467-1471).
In a preferred embodiment, the composition is effected using components which become specifically concentrated in the cells and/or organs to be treated. In this connection, the composition of the liposomes can, for example, be selected such that the liposomes are additionally provided with molecules, such as antibodies, charged lipids or lipids which are modified with hydrophilic head groups, so that the composition becomes preferentially concentrated in the cells and/or organs to be treated. Such a composition, containing molecules which are specifically directed against tumor cells, virus-infected cells and/or organs, increases the therapeutic effect of the drugs and at the same time reduces the toxicity for uninfected tissues.
The compositions can be processed to give a remedy which, in addition to the compounds according to the invention and, where appropriate, the organic carrier, also comprises customary excipients and/or diluents and/or auxiliary substances. Examples of customary excipients are mannitol, glucose, albumins or the like, while physiological sodium chloride solutions or a 5% glucose solution is in the main used as the diluent. Furthermore, it is customary to buffer the solutions with suitable reagents, for example phosphates. In addition to this, it is possible to add all the other agents which are customary for preparing pharmaceutical remedies, provided they do not attack the composition consisting of the organic carrier and the compounds according to the invention. The remedy can be administered either as an infusion solution or else orally.
However, the conversion into amphiphilic glyceryl nucleotides does not only have the effects of increasing the resistance to enzymic hydrolysis and significantly widening the possible administration forms; it also surprisingly optimizes cytostatic and virustatic effects.
The amphiphilic glyceryl nucleotides can be employed against malignant diseases of the hematopoietic cells and solid tumors. As a result of the superior cytostatic effect, there are far fewer serious side effects. It is possible to employ higher doses of the cytostatically active compounds according to the invention and therapy can be carried out in chronological intervals.
Surprisingly, the nucleoside phosphate analogs according to the invention also exhibit virustatic effects such that they can be used in the chemotherapy of viral infections and for overcoming drug resistances, as, for example, in the case of herpes, hepatitis and AIDS.
The invention therefore also relates to the use of compounds according to the invention for treating cancer diseases, such as leukemia, lung cancer, intestinal cancer, cancer of the central nervous system, melanomas, ovarian cancer, kidney cancer, prostate cancer and breast cancer; and also for treating viral diseases, such as AIDS, hepatitis A, B and C and herpes.
The following examples explain the invention without, however, restricting it to these examples.